Pierre Labauge

Truncating mutations in CCM1 , encoding KRIT1, cause hereditary cavernous angiomas

Cavernous angiomas are vascular malformations mostly located in the central nervous system and characterized by enlarged capillary cavities without intervening brain parenchyma. Clinical symptoms include seizures, haemorrhage and focal neurological deficits. Cavernous angiomas prevalence is close to 0.5% in the general population. They may be inherited as an autosomal dominant condition in as much as 50% of cases. Cerebral cavernous malformations (CCM) loci were previously identified on 7q, 7p and 3q (refs 4,5). A strong founder effect was observed in the Hispano-American population, all families being linked to CCM1 on 7q (refs 4,7). CCM1 locus assignment was refined to a 4-cM interval bracketed by D7S2410 and D7S689 ( ref. 8). Here we report a physical and transcriptional map of this interval and that CCM1, a gene whose protein product, KRIT1, interacts with RAP1A (also known as KREV1; ref. 9), a member of the RAS family of GTPases, is mutated in CCM1 families. Our data suggest the involvement of the RAP1A signal transduction pathway in vasculogenesis or angiogenesis.

Genetics of cavernous angiomas

Cerebral cavernous malformations (CCM) are vascular malformations that can occur as a sporadic or a familial autosomal dominant disorder. Clinical and cerebral MRI data on large series of patients with a genetic form of the disease are now available. In addition, three CCM genes have been identified: CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10. These recent developments in clinical and molecular genetics have given us useful information about clinical care and genetic counselling and have broadened our understanding of the mechanisms of this disorder.

Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy) is a small-artery disease of the brain caused by NOTCH3 mutations that lead to an abnormal accumulation of NOTCH3 within the vasculature. We aimed to establish whether immunostaining skin biopsy samples with a monoclonal antibody specific for NOTCH3 could form the basis of a reliable and easy diagnostic test. We compared the sensitivity and specificity of this method in two groups of patients suspected of having CADASIL with complete scanning of mutation-causing exons of NOTCH3 (in a retrospective series of 39 patients) and with limited scanning of four exons that are mutation hotspots (prospective series of 42 patients). In the retrospective series skin biopsy was positive in 21 (96%) of the 22 CADASIL patients examined and negative in all others; in the prospective series, seven of the 42 patients had a positive skin biopsy whereas only four had a mutation detected by limited NOTCH3 scanning. Our immunostaining technique is highly sensitive (96%) and specific (100%) for diagnosis of CADASIL.

Hereditary cerebral cavernous angiomas: clinical and genetic features in 57 French families

BACKGROUNDnCavernous angiomas, which are vascular malformations mostly located in the central nervous system, may be inherited as an autosomal dominant disorder known as familial cerebral cavernoma (FCC). FCC has been studied in Hispanoamerican families, in which a strong founder effect was shown. We studied the families of 57 non-Hispanic patients with cavernous angiomas.nnnMETHODSnAll 28 neurosurgery centres in France collaborated in the study. Inclusion criteria were: families of index patients known to have at least one clinically affected relative, and families of index patients with multiple cavernous angiomas who initially presented as sporadic cases. Clinical and cerebral magnetic resonance imaging (MRI) investigations were done in all patients and in other at-risk individuals who consented to take part.nnnFINDINGSnOn MRI, 16 of 22 sporadic index patients had relatives with cavernous angiomas. 51 multiple-case families, including 100 patients with symptoms and 164 symptom-free individuals had MRI lesions. Most FCC patients had multiple lesions and there was a strong correlation between number of lesions and age (p<0.01). The sensitivity of gradient-echo sequences was higher than that of standard MRI for detection of small cavernous angiomas. Pattern of inheritance was autosomal dominant, with incomplete clinical penetrance. The occurrence of de-novo mutations was strongly suggested in some families.nnnINTERPRETATIONnNeuroimaging penetrance of FCC is much higher than clinical penetrance. 75% of sporadic cases with multiple lesions are in fact familial cases. The proportion of patients developing clinical symptoms is higher in the hereditary form than in the sporadic form of the disorder.

The natural history of familial cerebral cavernomas: a retrospective MRI study of 40 patients

Abstract Our objective was to determine the natural history and prognostic factors of familial forms of cerebral cavernous malformations (CCM). Cavernomas are one of the most common central nervous system vascular malformations. Familial CCM is increasingly diagnosed, but little is known about its natural history. In a national survey, we analysed clinical and MRI features of 173 patients from 57 unrelated French families. Of these 40 had undergone at least two clinical and MRI examinations. Occurrence of haemorrhage, new lesions, change in signal intensity and size of lesions have been studied by comparison between first and last MRI studies. The CCM were classified according to Zabramski et al. Mean follow-up was 3.2 years (range 0.5–6.5 years). We followed 232 cavernomas (mean 5.9 per patient, range 1–17). Serial MRI demonstrated changes in 28 patients (70 %). Bleeding occurred in 21 lesions (9.1 %) in 14 patients (35 %). The haemorrhagic risk was 2.5 % per lesion-year, higher in type I and brain-stem CCM. We saw 23 new lesions appear in 11 patients (27.5 %), with an incidence of 0.2 lesions per patient year. Signal change was observed in 11 patients (27.5 %), in 14 lesions (6 %), while 9 lesions (3.9 %) in 9 patients (22.5 %) changed significantly in size.

An association between autosomal dominant cerebral cavernomas and a distinctive hyperkeratotic cutaneous vascular malformation in 4 families.

Cerebral cavernomas (CCMs) are vascular malformations that may be inherited as an autosomal dominant condition for which a gene, CCM1, was mapped to chromosome 7. Poorly defined cutaneous malformations were sometimes described in association with CCMs. During a national survey, 57 French CCM families were studied. Co‐occurrence of CCMs and a distinctive cutaneous vascular malformation was observed in 4 families. Ten individuals belonging to these families showed similar hyperkeratotic cutaneous capillary venous malformations (HCCVMs). In 3 families, the histology showed orthokeratosis and hyperkeratosis as well as dilated capillaries in the dermis extending to the hypodermis and confirmed the diagnosis of HCCVM. Genetic analysis strongly supports linkage of these families to the CCM1 locus on chromosome 7. The HCCVM seems to be a peculiar cutaneous vascular malformation associated with CCMs. These data strongly suggest that HCCVMs and CCMs in these families are due to the same genetic abnormality. Ann Neurol 1999;45:250–254

Clinical features of cerebral cavernous malformations patients with KRIT1 mutations

Cerebral Cavernous Malformations (CCM/OMIM 604214) are vascular malformations causing seizures and cerebral hemorrhages. They occur as a sporadic and autosomal dominant condition, the latter being characterized by the presence of multiple CCM lesions. Stereotyped truncating mutations of KRIT1, the sole CCM gene identified so far, have been identified in CCM1 linked families but the clinical features associated with KRIT1 mutations have not yet been assessed in a large series of patients. We conducted a detailed clinical, neuroradiological and molecular analysis of 64 consecutively recruited CCM families segregating a KRIT1 mutation. Those families included 202 KRIT1 mutation carriers. Among the 202 KRIT1 mutation carriers, 126 individuals were symptomatic and 76 symptom‐free. Mean age at clinical onset was 29.7 years (range, 2–72); initial clinical manifestations were seizures in 55% of the cases and cerebral hemorrhages in 32%. Average number of lesions on T2 weighted MRI was 4.9 (±7.2) and on gradient echo sequences 19.8 (±33.2). Twenty‐six mutation carriers harbored only one lesion on T2‐weighted MRI, including 4 mutation carriers, aged from 18 to 55 yr‐old, who presented only one CCM lesion both on T2‐weighted and on highly sensitive gradient echo MRI sequences. Five symptom free mutation carriers, aged from 27 to 48 yr‐old, did not have any detectable lesion both on T2WI and gradient echo MRI sequences. Within KRIT1/CCM1 families, both clinical and radiological penetrance are incomplete and age dependent. Importantly for genetic counseling, nearly half of the KRIT1 mutation carriers aged 50 or more are symptom‐free. The presence of only one lesion, even when using gradient echo MRI sequences, can be observed in some patients with an hereditary form of the disease. Incomplete neuroradiological penetrance precludes the use of cerebral MRI to firmly establish a non carrier status, even at an adult age and even when using highly sensitive gradient echo MRI. Altogether these data suggest that the hereditary nature of the disorder may be overlooked in some mutation carriers presenting as sporadic cases with a unique lesion. Ann Neurol 2004

Identical genetic locus for Baltic and Mediterranean myoclonus

Genetic linkage analysis shows that Baltic and Mediterranean myoclonus, two forms of progressive myoclonus epilepsy, are closely linked to marker D21S113 on the long arm of chromosome 21. Baltic and Mediterranean myoclonus are most probably due to mutations of the same gene.

De novo lesions in familial form of cerebral cavernous malformations: clinical and MR features in 29 non-Hispanic families

BACKGROUNDnTo evaluate clinical and MR features of de novo lesions (DNL) in the familial form of cerebral cavernous malformation (CCM) in 40 patients belonging to 29 unrelated non-Hispanic families.nnnMETHODSnForty patients followed up by serial cerebral MR examinations were included in this retrospective study. First and last available MR examinations were retrospectively analyzed and compared for each patient to diagnose DNL. Gradient-echo (GRE) sequences were performed in only 11 of the 40 patients and were not considered for this study. Incidence of DNL was evaluated in terms of lesions/patient-year. All DNL were characterized by their clinical and MR features (location, size, type). Type of CCM was determined according to the classification of Zabramski (1994). Patient groups with and without DNL were compared for sex, age, number of pre-existing CCMs, and follow-up.nnnRESULTSnTwenty-three DNL were recorded in 11 patients (27.5%) and the incidence was 0.2 lesions/patient-year (mean follow-up = 3.2 years). All but one DNL were asymptomatic. Twenty DNL were supratentorial and three were infratentorial. Mean diameter was 8 mm (2-35 mm). Six DNL were classified as type 1 (subacute hemorrhage), six as type 2 (hemorrhages and thromboses of varying ages) and 11 as type 3 (chronic hemorrhage with hemosiderin staining). No statistical difference between groups was found in terms of sex, age, or number of pre-existing CCMs. On the other hand, duration of follow-up was significantly longer in the group with DNL.nnnCONCLUSIONnThe occurrence of DNL seems to be a hallmark of the familial form of CCM in non-Hispanic families as well as in Hispanic families. Such DNL are usually asymptomatic and are mainly classified as type 3 (chronic hemorrhage with hemosiderin staining). Within the limits of the retrospective study design and potential selection bias introduced by the varying indications for MR scanning, it does seem that DNL may occur at any time in the lifespan of CCM patients, and occurrence does not seem to depend on age, sex, or the total number of pre-existing lesions.

Familial form of cerebral cavernous malformations: evaluation of gradient-spin-echo (GRASE) imaging in lesion detection and characterization at 1.5 T

The purpose of this study was to evaluate the turbo gradient-spin-echo sequence (GRASE) in the MR assessment of the familial form of cerebral cavernous malformations (CCM). Twenty-one patients (15 male, six female) aged from 21 to 68xa0years (mean = 42.2xa0years) were prospectively examined with cerebral MR imaging, including T2-weighted turbo gradient-spin-echo (TGSE), turbo spin-echo (TSE) and gradient-echo (GRE) sequences. All sequences were performed in the same plane, the same matrix and the same field of view and were analyzed for signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), susceptibility effects, number of CCM, size of CCM and signal of CCM. It was found that SNR and CNR in the TGSE sequence were significantly inferior to those in both TSE and GRE sequences. TGSE and TSE sequences were significantly less prone to susceptibility effects than the GRE sequence. The sensitivity of TGSE and TSE sequences in detecting CCM was significantly lower than that of the GRE sequence. TGSE and TSE sequences provided comparable information about CCM size and signal. It was concluded that GRASE imaging was less sensitive than the GRE sequence in the detection of CCM and provided information similar to that yielded by the TSE sequence in the characterization of lesions, but with a higher number of artifacts. GRASE imaging cannot therefore replace TSE or GRE sequences in the MR evaluation of the familial form of CCM.